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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aging process in higher mammals is increasingly being shown to feature a potentially substantial contribution from the longitudinal deterioration of normative stem cell dynamics seen with the passage of time. The precise mechanistic sequence producing this phenomenon is not entirely understood, but recent evidence has strongly implicated intracellular downstream effectors of endocrinologic pathways thought to be engaged by the obese state, specifically the insulin, IGF-1, and leptin signaling pathways. Among the intracellular effectors of these signals, a uniquely potent influence on stem cell dynamics may be attributable to Rho/ROCK, JAK kinase activity and STAT3 activity. In particular, it has already been shown that specific tyrosine kinase activities, such as that seen with Rho kinase, are presently thought to be associated with adverse health outcomes in numerous clinical contexts. Furthermore, the Rho GTPase is thought to be contributing to end-stage renal disease. However, in addition to its contribution to organ system dysfunction, the Rho/ROCK pathway has recently been shown to be activated by insulin and IGF-1, providing a tantalizing connection to nutrition and aging science. The JAK-STAT pathway, in contrast, has long been associated with pro-inflammatory cytokines, but has recently been implicated in leptin signaling as well. Importantly, JAK-STAT signaling has, similarly to Rho/ROCK signaling, been implicated as capable of accelerating stem cell proliferation. The implications of these recent determinations, in light of the recent finding of telomere attrition in humans associated with obesity, are that the intracellular determinants of aging may already be known, and the known common influence of these signaling elements on longitudinal stem cell dynamics is a pronounced induction of proliferation, an elevation that has been linked to the pathologic evolution of longitudinal organ-level dysfunction and the organismal-level physiologic decline seen with the inexorable passage of time. Besides the obvious utility for the management for human age-related dysfunction that investigation of pharmacologic inhibitors of these proteins would provide, interventions such as caloric restriction and possibly intermittent fasting may beneficially influence stem cell proliferation dynamics and reduce intracellular correlates of mitogenic drive. Integrating the findings present in the present body of research may reveal endocrinological states that are compatible with longevity, and will also provide novel insight into the specific proteomic determinants of age-related physiologic decline, ushering in a new epoch of medicine that fosters the management of the "pre-etiopathology" of chronic disease and disability of aging, therefore mitigating the suffering widely thought to be inherent in the latter stages of life.
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PMID:RhoA, Rho kinase, JAK2, and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1, and leptin may all conspire to promote stem cell exhaustion. 1622 46

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.
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PMID:Effect of obesity on insulin signaling through JAK2 in rat aorta. 1623 56

Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-gamma-coactivator-1alpha, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.
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PMID:Fat storage in adipocytes requires inactivation of leptin's paracrine activity: implications for treatment of human obesity. 1632 4

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.
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PMID:Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. 1672 88

Leptin has direct effects not only on neuroendocrine function and metabolism, but also on T cell-mediated immunity. We report in this study that leptin receptor (ObR) is expressed on resting normal mouse CD4(+), CD8(+), B cells, and monocyte/macrophages. ObR expression is up-regulated following cell activation, but with different kinetics, in different lymphocyte subsets. Leptin binding to ObR results in increased STAT-3 activation in T cells, with a different activation pattern in resting vs anti-CD3 Ab stimulated T cells. Leptin also promotes lymphocyte survival in vitro by suppressing Fas-mediated apoptosis. B lymphocytes appear to be more susceptible to the antiapoptotic effects of leptin, and they show higher surface expression of ObR, compared with T cells. Moreover, CD4(+) T cells isolated from ObR-deficient mice displayed a reduced proliferative response, compared with normal controls. Furthermore, ObR/STAT-3-mediated signaling in T lymphocytes is decreased in the diet-induced obese mouse model of obesity and leptin resistance. In summary, our findings show that the ObR is expressed on normal mouse lymphocyte subsets, that leptin plays a role in lymphocyte survival, and that leptin alters the ObR/STAT-3-mediated signaling in T cells. Taken together, our data further support the notion that nutritional status acting via leptin-dependent mechanisms may alter the nature and vigor of the immune response.
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PMID:Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. 1675 22

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.
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PMID:Adipokines that link obesity and diabetes to the hypothalamus. 1687 74

Obesity is a state of leptin resistance in which the membrane leptin receptor and the JAK-STAT pathway are blocked. This leads to increased intracellular concentrations of lipid metabolites, increased non-oxidative metabolism by adipocytes, and stimulation of the cell estrogen cycle. These factors are potentially oncogenic via the shared mitogen-activated protein kinase (MAPK), mitogen/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) cellular pathways.
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PMID:Leptin, estrogens and cancer. 1691 96

Leptin is best known as a key satiety factor and it is now appreciated that leptin has many additional biological functions. Our previous study suggested that leptin-resistant obesity might exacerbate 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in vivo. Here, we ask whether leptin might protect neuronal cells against 1-methyl-4-pyridinium (MPP+)-induced cell death. We used differentiated SH-SY5Y cells and investigated plausible cytoprotective signalling mechanisms. When SH-SY5Y cells were maintained under serum-free conditions for 48 h, MPP+ (1 mM) reduced cell viability to 66.8% of the drug-free control, and leptin significantly inhibited cell death in a dose-dependent manner. Among inhibitors of known leptin signalling pathways, a PI-3K inhibitor inhibited the protective effect of leptin during MPP+ exposure, whereas inhibitors affecting the Janus kinase/signal transducers and activators of transcription (JAK/STAT) or mitogen-activated protein kinase (MAPK) pathways did not influence cell viability. We used immunoblotting to show that the PI-3K/Akt pathway was involved in the effect of leptin on cell viability. In conclusion, our results show that leptin exercises a cytoprotective effect against MPP+ -induced cell death and that this effect is dependent on activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway in SH-SY5Y cells. The data tend to support our previous results in vivo.
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PMID:Leptin inhibits 1-methyl-4-phenylpyridinium-induced cell death in SH-SY5Y cells. 1697 75

One of the major manifestations of obesity is an increased production of the adipocyte-derived 16-kDa peptide leptin, which acts mainly on hypothalamic leptin receptors. Leptin receptors are widely distributed in various tissues, including the heart. Whereas increased plasma leptin levels have been reported in patients with congestive heart failure, systemic alterations induced by obesity can affect cardiac hypertrophy, and the direct effects of leptin on cardiac structure and function still remain to be determined. We first exposed primary cardiac myocytes from neonatal rats to leptin for 48 h. This resulted in a significant increase in myocyte long-axis length (P < 0.05 at 50 ng/ml) but not in the short-axis width. Leptin induced the rapid phosphorylation of STAT3 and its DNA binding in cardiac myocytes. Administration of a JAK2 inhibitor, AG-490, completely inhibited all of these effects by leptin. Furthermore, we examined the effect of continuous infusion of leptin for 4 wk following myocardial infarction in mice. Echocardiography demonstrated that left ventricular fractional shortening in the leptin-infused group (28.4 +/- 2.8%) was significantly higher than that in the PBS-infused group (18.4 +/- 2.2%) following myocardial infarction. Interestingly, left ventricular diastolic dimension in the leptin-infused group (4.56 +/- 0.12 mm) was also higher than that in the PBS-infused group (4.13 +/- 0.09 mm). These results demonstrate that leptin induces the elongation of cardiac myocytes via a JAK/STAT pathway and chronic leptin infusion causes eccentric dilatation with augmented systolic function after myocardial infarction.
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PMID:Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. 1722 Jan 91

Various epidemiologic studies have shown that obesity is associated with hepatocellular carcinoma. Leptin, the key player in the regulation of energy balance and body weight control, also acts as a growth factor on certain organs in both normal and disease states. It is plausible that leptin acts to promote hepatocellular carcinogenesis directly affecting malignant properties of liver cancer cells. However, a direct role for leptin in hepatocellular carcinoma has not been shown. In this study, we analyzed the role of leptin and the mechanism(s) underlying its action in hepatocellular carcinoma cells, which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of both HepG2 and Huh7 cells and involves activation of signal transducers and activators of transcription 3 (STAT3), AKT, and extracellular signal-regulated kinase (ERK) signaling pathways. Leptin-induced phosphorylation of ERK and AKT was dependent on Janus-activated kinase (JAK)/STAT activation. Intriguingly, we also found that leptin potently induces invasion of hepatocellular carcinoma cells in Matrigel invasion and electric cell-substrate impedance-sensing assays. Leptin-stimulated invasion was effectively blocked by pharmacologic inhibitors of JAK/STAT and, to a lesser extent, by ERK and phosphatidylinositol 3-kinase (PI3K) inhibition. Importantly, leptin also induced the migration of both HepG2 and Huh7 cells on fibronectin matrix. Inhibition of JAK/STAT, ERK, and PI3K activation using pharmacologic inhibitors effectively blocked leptin-induced migration of HepG2 and Huh7 cells. Taken together, these data indicate that leptin promotes hepatocellular carcinoma growth, invasiveness, and migration and implicate the JAK/STAT pathway as a critical mediator of leptin action. Our findings have potential clinical implications for hepatocellular carcinoma progression in obese patients.
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PMID:Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. 1736 67


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